Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Huntington's disease (HD) is an inherited neuropsychiatric degenerative process characterized by movement disorder, dementia, and, often, affective disorder (AfD) (seen in 38% of patients). Depression in HD is not just an understandable reaction to fatal illness: 10% of HD patients develop mania; AfD can occur 20 yr before neurological signs; and mood disorders are not randomly distributed, but occur in a subset of HD families. This evidence suggests that AfD in HD relates to brain pathophysiology. With its clear neuropathology, HD is proposed as one model for biological underpinnings of idiopathic AfD. There is striking atrophy and neuronal loss in HD neostriatum, particularly caudate. Caudate has rich connections to the limbic system. It is hypothesized that AfD in HD relates to dysfunction of the part of the neostriatum damaged earliest, dorsal medial caudate. Preliminary studies on neuropathological differences between HD patients with and without AfD are discussed. HD neurochemistry is reviewed, emphasizing the excitotoxin hypothesis, which involves dysfunction of the glutamate neurotransmitter system in HD (especially the NMDA receptor, which contains a channel with a phencyclidine (PCP) binding site). Based on the HD model, it is suggested that the glutamate system (particularly NMDA receptors) be examined in idiopathic AfD.
Mol Chem Neuropathol 1990 Mar
PMID:Huntington's disease as a model for mood disorders. Clues from neuropathology and neurochemistry. 214 28

Both mania and bipolar depression have been associated with decrements in the activity of the sodium and potassium-activated adenosine triphosphatase (Na,K-ATPase) membrane pump. Although the role of this observation in the pathophysiology of bipolar illness is unclear, it has been proposed that this defect could be central to the pathogenesis of the illness. In an effort to test this hypothesis, the authors examined the efficacy of lithium pretreatment in attenuating behavioral changes secondary to acute administration of a single intracerebroventricular (i.c.v.) dose of the Na,K-ATPase-inhibiting compound, ouabain, in the Sprague-Dawley rat. Ouabain (10(-3)M) significantly decreased motor activity in automated activity monitors. Lithium pretreatment for 7 d totally prevented this effect. These preliminary data suggest that i.c.v. ouabain administration in the rat may prove to be a viable animal model for bipolar illness.
Mol Chem Neuropathol 1997 May
PMID:Lithium prevents ouabain-induced behavioral changes. Toward an animal model for manic depression. 927 Oct 6

Recurrent major depression, RMD, is characterized by the occurrence of depressive episodes in the absence of mania and/or hypomania. In linkage studies, RMD (or, in general, unipolar depression) are frequently grouped together with bipolar illnesses into a broad definition of affective disorders. However, twin studies suggest that RMD and bipolar disorders might have different genetic determinants. The objective of this study was to test a set of families with RMD for linkage to chromosomes that have been recently proposed to contain susceptibility loci for bipolar disorders: chromosomes 16, 18, 21 and the short arm of chromosome 4. We analysed five large families from the northern part of Sweden ascertained through a proband with RMD and containing several patients with RMD. For the genetic analysis, we included only severely affected individuals (those who had at least three episodes that required medical treatment) to increase the chances of finding a larger degree of genetic determination. The genetic model led to a total disease prevalence of 5% in females and 3% in males. We did not find significant evidence for linkage to any of the candidate chromosomes in the combined family set. Only one of the families showed a slight indication for linkage with markers from the pericentromeric region of chromosome 18. A genome scan analysis on an extended collaborative family material with severely affected individuals with RMD should be performed to evaluate whether RMD and bipolar disorders have a different genetic etiology.
Mol Psychiatry 1998 Mar
PMID:Linkage analysis of candidate loci in families with recurrent major depression. 957 41

Bipolar spectrum disorders are recurrent illnesses characterized by episodes of depression, hypomania, mania or the appearance of mixed states. Great variability is evident in the frequency of episode recurrence and duration. In addition to regular circannual episodes, a spectrum of cycle frequencies has been observed, from the classical rapid cycling (RC) pattern of four or more episodes per year, to those with distinct shifts of mood and activity occurring within a 24-48 h period, described as ultra-ultra rapid cycling (UURC) or ultradian cycling. RC has a female preponderance, and occurs with greater frequency premenstrually, at the puerperium and at menopause. Tricyclic antidepressants and MAOIs, both of which increase functional monoamines norepinephrine, dopamine and serotonin, are known to precipitate mania or rapid-cycling in an estimated 20-30% of affectively ill patients. We have recently reported a strong association between velo-cardio-facial syndrome (VCFS) patients diagnosed with rapid-cycling bipolar disorder, and an allele encoding the low enzyme activity catechol-O-methyltransferase variant (COMT L). Between 85-90% of VCFS patients are hemizygous for COMT. Homozygosity for the low activity allele (COMT LL) is associated with a 3-4 fold reduction of COMT enzyme activity compared with homozygotes for the high activity variant (COMT HH). There is nearly an equal distribution of L and H alleles in Caucasians. Individuals with COMT LL would be expected to have higher levels of transynaptic catecholamines due to a reduced COMT degradation of norepinephrine and dopamine. We therefore hypothesized that the frequency of COMT L would be greater in RC BPD ascertained from the general population. Significantly, we found that the frequency of COMT L was higher in the UURC variant of BPD than among all other groups studied (P = 0.002). These findings indicate that COMT L could represent a modifying gene that predisposes to ultra-ultra or ultradian cycling in patients with bipolar disorder.
Mol Psychiatry 1998 Jul
PMID:Ultra-ultra rapid cycling bipolar disorder is associated with the low activity catecholamine-O-methyltransferase allele. 970 45

Fringe was originally identified as a novel secreted signaling protein with a key role in wing formation of Drosophila. Three vertebrate fringe homologues, Radical, Lunatic and Manic fringe, were also identified, and have been shown to play major roles in neurogenesis during development. However, the expression and roles of vertebrate fringe homologues in the adult brain remain to be elucidated. We isolated the cDNA encoding rat Radical fringe (334 amino acids) from rat embryos, and found its mRNA to be most abundantly expressed in the adult rat brain by Northern blotting analysis. The localization of Radical fringe mRNA in the adult rat brain was also examined by in situ hybridization. The mRNA was abundantly expressed in most neurons, but not glial cells, throughout the brain. Notch signaling was shown to negatively modulate the stability of neurites and connections in postmitotic primary neurons. Furthermore, genetic evidence indicated that fringe modulated the Notch signaling pathway. Therefore, we examined the effects of Radical fringe on the Notch signaling pathway in primary rat neurons of the cerebral cortex using recombinant rat Radical fringe protein. Radical fringe protein significantly inhibited expression of the Notch effector Hes1 mRNA in primary neurons. These results indicated that Radical fringe functions by inhibiting Notch signaling in postmitotic neurons of the brain.
Brain Res Mol Brain Res 2001 Jan 31
PMID:Radical fringe negatively modulates Notch signaling in postmitotic neurons of the rat brain. 1116 80

Bipolar affective disorder (BPAD), also known as manic depressive illness, is a severe psychiatric disorder characterized by episodes of mania and depression. It has a lifetime prevalence of approximately 1% in all human populations. In order to identify chromosomal regions containing genes that play a role in determining susceptibility to this psychiatric condition, we have conducted a complete genome screen with 382 markers (average marker spacing of 9.3 cM) in a sample of 75 BPAD families which were recruited through an explicit ascertainment scheme. Pedigrees were of German, Israeli and Italian origin, respectively. Parametric and non-parametric linkage analysis was performed. The highest two-point LOD score was obtained on 8q24 (D8S514; LOD score = 3.62), in a region that has not attracted much attention in previous linkage studies of BPAD. The second best finding was seen on 10q25-q26 (D10S217; LOD score = 2.86) and has been reported in independent studies of BPAD. Other regions showing 'suggestive' evidence for linkage localized to 1p33-p36, 2q21-q33, 3p14, 3q26-q27, 6q21-q22, 8p21, 13q11 and 14q12-q13. In addition, we aimed at detecting possible susceptibility loci underlying genomic imprinting by analyzing the autosomal genotype data with the recently developed extension of the GENEHUNTER program, GENEHUNTER-IMPRINTING. Putative paternally imprinted loci were identified in chromosomal regions 2p24-p21 and 2q31-q32. Maternally imprinted susceptibility genes may be located on 14q32 and 16q21-q23.
Hum Mol Genet 2001 Dec 01
PMID:A genome screen for genes predisposing to bipolar affective disorder detects a new susceptibility locus on 8q. 1174 36

The evidence for the involvement of cholinergic muscarinic receptors in mania and depression is reviewed. Small pilot trials with cholinesterase inhibitors and muscarinic agonists suggest that stimulation of muscarinic receptors may produce an antimanic effect, possibly by activation of muscarinic M(4) receptors. It is concluded that it is not likely that currently used mood stabilizers, such as lithium, valproic acid and carbamazepine, work directly through muscarinic receptor mechanisms. Furthermore, the evidence indicates that antipsychotic agents used for mania are working through the common mechanism of antagonism of dopamine D(2) receptors, and interactions with muscarinic receptors do not play a key role. Finally, it is hypothesized that olanzapine has robust antimanic activity, due to blockade of dopamine D(2) receptors and antagonism of other monoaminergic receptors. Olanzapine may normalize mood due to antidepressant-like activities, such as 5-HT(2A) receptor antagonism and increasing cortical norepinephrine and dopamine.
Mol Psychiatry 2002
PMID:Role of the cholinergic muscarinic system in bipolar disorder and related mechanism of action of antipsychotic agents. 1198 96

Bipolar disorder (BPD) is a common disorder characterized by episodes of mania, hypomania and depression. The genetic background of BPD remains undefined, although several putative loci predisposing to BPD have been identified. We have earlier reported significant evidence of linkage for BPD to chromosome Xq24-q27.1 in an extended pedigree from the late settlement region of the genetically isolated population of Finland. Further, we established a distinct chromosomal haplotype covering a 19 cM region on Xq24-q27.1 co-segregating with the disorder. Here, we have further analyzed this X-chromosomal region using a denser marker map and monitored X-chromosomal haplotypes in a study sample of 41 Finnish bipolar families. Only a fraction of the families provided any evidence of linkage to this region, suggesting that a relatively rare gene predisposing to BPD is enriched in this linked pedigree. The genome-wide scan for BPD predisposing loci in this large pedigree indicated that this particular X-chromosomal region provides the best evidence of linkage genome-wide, suggesting an X-chromosomal gene with a major role for the genetic predisposition of BPD in this family.
Mol Psychiatry 2002
PMID:Bipolar disorder susceptibility region on Xq24-q27.1 in Finnish families. 1208 62

In a genome-wide linkage survey, we have previously shown evidence suggesting that the chromosome 22q12 region contains a susceptibility locus for bipolar disorder (BPD). Two independent family sets yielded lod scores suggestive of linkage at markers in this region near the gene G protein receptor kinase 3 (GRK3). GRK3 is an excellent candidate risk gene for BPD since GRK3 is expressed widely in the brain, and since GRKs play key roles in the homologous desensitization of G protein-coupled receptor signaling. We have also previously shown GRK3 expression to be induced by amphetamine in an animal model of mania using microarray-based expression profiling. To identify possible functional mutations in GRK3, we sequenced the putative promoter region, all 21 exons, and intronic sequence flanking each exon, in 14-22 individuals with BPD. We found six sequence variants in the 5'-UTR/promoter region, but no coding or obvious splice variants. Transmission disequilibrium analyses of one set of 153 families indicated that two of the 5'-UTR/promoter variants are associated with BPD in families of northern European Caucasian ancestry. A supportive trend towards association to one of these two variants (P-5) was then subsequently obtained in an independent sample of 237 families. In the combined sample, the P-5 variant had an estimated allele frequency of 3% in bipolar subjects, and displayed a transmission to non-transmission ratio of 26 : 7.7 (chi(2)=9.6, one-sided P value=0.0019). Altogether, these data support the hypothesis that a dysregulation in GRK3 expression alters signaling desensitization, and thereby predisposes to the development of BPD.
Mol Psychiatry 2003 May
PMID:Evidence that a single nucleotide polymorphism in the promoter of the G protein receptor kinase 3 gene is associated with bipolar disorder. 1280 34

Manic-depressive (bipolar) illness is a serious psychiatric disorder with a strong genetic predisposition. The disorder is likely to be multifactorial and etiologically complex, and the causes of genetic susceptibility have been difficult to unveil. Lithium therapy is a widely used pharmacological treatment of manic-depressive illness, which both stabilizes the ongoing episodes and prevents relapses. A putative target of lithium treatment has been the inhibition of the myo-inositol monophosphatase (IMPase) enzyme, which dephosphorylates myo-inositol monophosphate in the phosphatidylinositol signaling system. Two genes encoding human IMPases have so far been isolated, namely myo-inositol monophosphatase 1 (IMPA1) on chromosome 8q21.13-21.3 and myo-inositol monophosphatase 2 (IMPA2) on chromosome 18p11.2. In the present study, we have scanned for DNA variants in the human IMPA1 and IMPA2 genes in a pilot sample of Norwegian manic-depressive patients, followed by examination of selected polymorphisms and haplotypes in a family-based bipolar sample of Palestinian Arab proband-parent trios. Intriguingly, two frequent single-nucleotide polymorphisms (-461C>T and -207T>C) in the IMPA2 promoter sequence and their corresponding haplotypes showed transmission disequilibrium in the Palestinian Arab trios. No association was found between the IMPA1 polymorphisms and bipolar disorder, neither with respect to disease susceptibility nor with variation in lithium treatment response. The association between manic-depressive illness and IMPA2 variants supports several reports on the linkage of bipolar disorder to chromosome 18p11.2, and sustains the possible role of IMPA2 as a susceptibility gene in bipolar disorder.
Mol Psychiatry 2004 Jun
PMID:Examination of IMPA1 and IMPA2 genes in manic-depressive patients: association between IMPA2 promoter polymorphisms and bipolar disorder. 1469 25


1 2 3 4 5 6 7 8 9 Next >>